c-Met is a chimeric antigen receptor T-cell target for treating recurrent nasopharyngeal carcinoma.

BACKGROUND AIMS: Radiation therapy is the standard treatment for patients with nasopharyngeal carcinoma (NPC), but relapse occurs in 10% to 20% of patients. The treatment of recurrent nasopharyngeal carcinoma (rNPC) remains challenging. Chimeric antigen receptors (CAR)-T-cell therapy has achieved good outcomes in the treatment of leukemia and seems to be a promising therapeutic strategy for solid tumors. c-Met has been found to be highly expressed in multiple cancer types, and the activation of c-Met leads to the proliferation and metastasis of cancer cells. However, the expression of c-Met in rNPC tissues and whether it can be used as a target for CAR-T therapy in rNPC remain to be investigated. METHODS: We detected the expression of c-Met in 24 primary human rNPC tissues and three NPC cell lines and constructed two different antibody-derived anti-c-Met CARs, namely, Ab928z and Ab1028z. To estimate the function of these two different c-Met-targeted CAR-T cells, CD69 expression, cytotoxicity and cytokine secretion of CAR-T cells were assessed after coculture with target cells. A cell line-derived xenograft mouse model also was used to evaluate these two anti-c-Met CAR-T cells. Furthermore, we determined whether combination with an anti-EGFR antibody could promote the antitumor effect of CAR-T cells in a patient-derived xenograft mouse model. RESULTS: High c-Met expression was detected in 23 of 24 primary human rNPC tissues by immunohistochemistry staining and in three NPC cell lines by flow cytometry. Ab928z-T cells and Ab1028z-T cells showed significantly upregulated expression of CD69 after coculture with targeted cells. However, Ab1028z-T cells showed superior cytokine secretion and antitumor activity. Furthermore, Ab1028z-T cells effectively suppressed tumor growth compared with control CAR-T cells, and the combination with nimotuzumab further enhanced the tumor-clearing ability of Ab1028z-T cells. CONCLUSIONS: We found that c-Met is highly expressed in rNPC tissues and confirmed its potential as a CAR-T target for rNPC. Our study provides a new idea for the clinical treatment of rNPC.

Hemorrhagic pericardial effusion resulting in constriction in hereditary hemorrhagic telangiectasia.

BACKGROUND: We report the first ante-mortem diagnosis of hemorrhagic pericardial effusion in hereditary hemorrhagic telangiectasia resulting in constriction; the case also demonstrates the unusual but well-described complication of right-sided heart failure requiring extracorporeal membrane oxygenation (ECMO) support after pericardiectomy. CASE PRESENTATION: A previously healthy 48 year old man with a strong family history of Osler-Weber-Rendu disease presented to our institution with signs and symptoms of advance heart failure. His workup demonstrated a thickened pericardium and constrictive physiology. He was brought to the operating room where old clot and inflamed tissue were appreciated in the pericardial space and he underwent complete pericardiectomy under cardiopulmonary bypass. Separation from bypass, hampered by the development of right ventricular dysfunction and profound vasoplegia, required significant pressor and inotropic support. The right heart dysfunction and vasoplegia worsened in the early postoperative period requiring a week of ECMO after which his right ventricle recovered and he was successfully de-cannulated. CONCLUSION: Given the poor outcome of severe postoperative right ventricular failure after pericardiectomy, with high central venous pressure, a low gradient between central venous and pulmonary artery pressures and high vasopressor requirements, ECMO should be instituted promptly.

Perioperative Individualized Goal Directed Therapy for Cardiac Surgery: A Historical-Prospective, Comparative Effectiveness Study.

INTRODUCTION: Cardiac surgery patients are at increased risk for post-operative complications and prolonged length of stay. Perioperative goal directed therapy (GDT) has demonstrated utility for non-cardiac surgery, however, GDT is not common for cardiac surgery. We initiated a quality improvement (QI) project focusing on the implementation of a GDT protocol, which was applied from the immediate post-bypass period into the intensive care unit (ICU). Our hypothesis was that this novel GDT protocol would decrease ICU length of stay and possibly improve postoperative outcomes. METHODS: This was a historical prospective, QI study for patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB). Integral to the QI project was education towards all associated providers on the concepts related to GDT. The protocol involved identifying patient specific targets for cardiac index and mean arterial pressure. These targets were maintained from the post-CPB period to the first 12 h in the ICU. Statistical comparisons were performed between the year after GDT therapy was launched to the last two years prior to protocol implementation. The primary outcome was ICU length of stay. RESULTS: There was a significant decrease in ICU length of stay when comparing the year after the protocol initiation to years prior, from a median of 6.19 days to 4 days (2017 vs. 2019, p < 0.0001), and a median of 5.88 days to 4 days (2018 vs. 2019, p < 0.0001). Secondary outcomes demonstrated a significant reduction in total administered volumes of inotropic medication(milrinone). All other vasopressors demonstrated no differences across years. Hospital length of stay comparisons did not demonstrate a significant reduction. CONCLUSION: These results suggest that an individualized goal directed therapy for cardiac surgery patients can reduce ICU length of stay and decrease amount of inotropic therapy.

CDR1as is overexpressed in laryngeal squamous cell carcinoma to promote the tumour's progression via miR-7 signals.

OBJECTIVES: To investigate the roles played by the circular RNA (circRNA) molecule ciRS-7 (CDR1as) and tumour suppressor miRNA-7 (miR-7) in laryngeal squamous cell carcinoma (LSCC). METHODS: Specimens of LSCC tissue (n = 30) and corresponding relative normal tissue (n = 30) were collected to determine their levels and clinical significance of CDR1as/mir-7 expression. The CDR1as and miR-7 were overexpressed in LSCC cells to investigate its function and mechanism in vitro and in vivo. RESULTS: Patients with high TNM stages, poorly differentiated tumours, lymph node metastases and poor prognosis had high CDR1as levels but low miR-7 levels. CDR1 expression was negatively associated with miR-7 expression in LSCC. Overexpression of CDR1as in vitro enhanced cell vitality, and promoted the proliferation, migration, and invasion of two LSCC cell lines (Hep2 and AMC-HN-8.) However, these effects could be abrogated by knockdown of CDR1as or the forced expression of miR-7. Mechanistically, overexpressed CDR1 molecules functioned as miR-7 sponges and upregulated the key targets of miR-7, CCNE1, and PIK3CD in Hep2 and AMC-HN-8 cells. In vivo studies demonstrated the tumourigenic role of CDR1as. Overexpression of CDR1as alone promoted tumour growth and increased expression of the proliferation indices ki-67, CCNE1, and PIK3CD. Although the tumour suppressor miR-7 effectively inhibited the tumour growth, this effect could be counteracted by co-treatment with CDR1as in vivo. CONCLUSION: CDR1as is an oncogene that promotes LSCC progression by regulating miR-7 signals.

Management of Complex Cardiac Issues in the Pregnant Patient.

Management of peripartum heart disease in the intensive care unit requires optimization of maternal hemodynamics and maintenance of fetal perfusion. This requires fetal monitoring and should address the parturient's oxygen saturation, hemoglobin, and cardiac output as it relates to uterine blood flow. Pharmacologic strategies have limited evidence pertaining to hemodynamic stabilization and fetal perfusion. There is some evidence that surgical management of critical mitral stenosis should be percutaneous when possible because cardiac bypass is associated with increased fetal mortality. Fetal monitoring strategies should address central organ perfusion because peripheral scalp pH has not been associated with improved fetal outcomes.